2XA3

crystal structure of the broadly neutralizing llama VHH D7 and its mode of HIV-1 gp120 interaction

Summary for 2XA3

• Entry DOI: 10.2210/pdb2xa3/pdb
• Descriptor: LLAMA HEAVY CHAIN ANTIBODY D7, SULFATE ION (3 entities in total)
• Functional Keywords: immune system
• Biological source: LAMA GLAMA (LLAMA)
• Total number of polymer chains: 1
• Total formula weight: 14283.51

Authors

Hinz, A.,Lutje Hulsik, D.,Forsman, A.,Koh, W.,Belrhali, H.,Gorlani, A.,de Haard, H.,Weiss, R.A.,Verrips, T.,Weissenhorn, W. (deposition date: 2010-03-29, release date: 2010-05-26, Last modification date: 2024-11-13)

Primary citation

Hinz, A.,Lutje Hulsik, D.,Forsman, A.,Koh, W.W.,Belrhali, H.,Gorlani, A.,de Haard, H.,Weiss, R.A.,Verrips, T.,Weissenhorn, W.
Crystal structure of the neutralizing Llama V(HH) D7 and its mode of HIV-1 gp120 interaction.
PLoS ONE, 5:e10482-e10482, 2010

PubMed Abstract: HIV-1 entry into host cells is mediated by the sequential binding of the envelope glycoprotein gp120 to CD4 and a chemokine receptor. Antibodies binding to epitopes overlapping the CD4-binding site on gp120 are potent inhibitors of HIV entry, such as the llama heavy chain antibody fragment V(HH) D7, which has cross-clade neutralizing properties and competes with CD4 and mAb b12 for high affinity binding to gp120. We report the crystal structure of the D7 V(HH) at 1.5 A resolution, which reveals the molecular details of the complementarity determining regions (CDR) and substantial flexibility of CDR3 that could facilitate an induced fit interaction with gp120. Structural comparison of CDRs from other CD4 binding site antibodies suggests diverse modes of interaction. Mutational analysis identified CDR3 as a key component of gp120 interaction as determined by surface plasmon resonance. A decrease in affinity is directly coupled to the neutralization efficiency since mutations that decrease gp120 interaction increase the IC50 required for HIV-1 IIIB neutralization. Thus the structural study identifies the long CDR3 of D7 as the key determinant of interaction and HIV-1 neutralization. Furthermore, our data confirm that the structural plasticity of gp120 can accommodate multiple modes of antibody binding within the CD4 binding site.

PubMed: 20463957
DOI: 10.1371/journal.pone.0010482

Experimental method

X-RAY DIFFRACTION (1.5 Å)